The present invention relates to the prevention and treatment of eye pain.
Pain is a nociceptive response to local stimulation in the body. Pain perception in the central nervous system requires the transmission of pain stimuli by the peripheral nerve fibres. When tissue is stimulated, whether thermally, mechanically or chemically, electrochemical signals are transmitted from the sensory nerve endings towards the spinal column, and from there towards the brain where pain is felt.
There are various kinds of pain, of highly diverse origins, the treatment of which is radically different depending on the type of pain and its aetiology. Eye pain is a particular form of pain which appears under many conditions, for instance accidental trauma, surgical procedures, uveitis, dry eye syndrome and diabetic neuropathies.
The medicinal products commonly used to treat eye pain are topical or systemic nonsteroidal anti-inflammatories, systemic analgesics, local anaesthetics and, in extreme cases, systemic opiates. These treatments have limited efficacy and systemic local side effects. Local anaesthetics act on pain by directly inhibiting nerve transmission. Their use is limited to brief administration under medical supervision because their mechanism of action induces inhibitory effects at the cellular level in fibroblasts or the surrounding neuronal cells. That is why, even if the pain sensation can be alleviated by local anaesthetics, tissue healing and physiology can be impaired. It is thus important to discover other analgesic agents, without anaesthetic activity, which are effective and well-tolerated when applied topically to the painful eye.
Opiates such as morphine sulphate are used systemically to treat severe eye pain, but they have many adverse effects, such as sedation, nausea, constipation and respiratory depression, which substantially limit their use, particularly for chronic eye pain. It has been shown that topical administration of morphine relieves pain associated with corneal lesions in dogs (Stiles et al. (2003) Am. J. Vet. Res., 64, 813-818) and in rats (Wenk et al. (2003) Pain, 105, 455-465) without retarding healing of the corneal wound (Stiles et al. (2003) Am. J. Vet. Res., 64, 813-818).
Perception, transmission and regulation of nociceptive inputs are subordinate to several neurotransmitters, in particular the enkephalins (Met-enkephalin and Leu-enkephalin). The latter are pentapeptides, endogenous opioids, first discovered in the mammalian brain (Hugues et al. (1975) Nature, 258, 577-580). They bind mainly to two receptor classes, μ- and δ-opioid receptors (Lord et al. (1977) Nature, 267, 495-499), which have different functions and distributions (Waksman et al. (1986) Proc. Natl. Acad. Sci., 83, 1523-1527).
The antinociceptive properties of the enkephalins have been shown after intracerebroventricular administration of exogenous enkephalins (Belluzi et al. (1976) Nature, 260, 625-626). However, this response is highly transient because these peptides are metabolized very rapidly by enzymes. Synthetic enkephalin analogues, modified to make them resistant to enzymatic degradation, have shown antinociceptive properties equal to those of morphine, but have also exhibited the same adverse side effects as morphine.
Furthermore, it is known that the enkephalins (Tyr-Gly-Gly-Phe-Met and Tyr-Gly-Gly-Phe-Leu) are physiologically inactivated by two zinc metallopeptidases, neprilysin (EC 3.4.24.11, NEP), which cleaves the Gly3-Phe4 bond (Malfroy et al. (1978) Nature, 276, 523-526), and aminopeptidase N (EC 3.4.11.2, APN), which cleaves the Tyr1-Gly2 bond of these peptides. (Waksman et al. (1985) Eur. J. Pharmacol., 117, 233-243; reviewed in Roques et al. (1993) Pharmacol. Rev., 45, 87-146). Inhibiting these two enzymatic activities by fully protecting enkephalins (Bourgoin et al. (1986) J. Pharm. Exp. Ther., 238, 360-366), reveals the pharmacological activities, particularly the analgesic and antidepressant activities (Roques (2000) Trends Pharmacol. Sci., 21, 475-483; Jutkiewicz et al. (2007) CNS Drugs Reviews, 13, 192-205), of these endogenous opioids, the enkephalins.
Aminophosphinic derivatives, “true” mixed inhibitors, i.e., inhibiting both APN and NEP, have been described in previous patents and publications (WO9818803; WO2010010106; Chen et al. (2000) J. Med. Chem., 43, 1398-1408; Chen et al. (2001) J. Med. Chem., 44, 3523-3530; Le Guen et al. (2003) Pain, 104, 139-148; Bonnard et al. (2015) Pharmacol. Res. Persp., 3(2), e00116, doi: 10.1002/prp2.116). Good antinociceptive activity, with a long duration of action, has been shown on numerous animal models of nociception after oral and/or iv administration (Chen et al. (2000) J. Med. Chem., 43, 1398-1408; Chen et al. (2001) J. Med. Chem., 44, 3523-3530; Le Guen et al. (2003) Pain, 104, 139-148; Bonnard et al. (2015) Pharmacol. Res. Persp., 3(2), e00116, doi: 10.1002/prp2.116).
The use of said compounds as topical ocular analgesics has never been disclosed or suggested. It has also never been shown that prodrugs of mixed inhibitors of NEP and APN could hydrolyse to give a compound capable of reaching its target, thus allowing a long-lasting analgesic response. One of the objects of this invention is thus to provide novel aminophosphinic-type compounds capable of inhibiting both of the enzymatic activities (neprilysin and aminopeptidase N) responsible for the degradation of enkephalins, the latter which can have action within the context of eye pain.
More particularly, the invention relates to compounds having the formula (I):R1—NH—CH(R2)—P(═O)(OH)—CH2—C(R3)(R4)—CONH—C(R5)(R6)—COOR7  (I)Wherein:R1 is                a hydrogen        an (acyloxy)alkyl carbamate group —C(═O)—O—C(R)(R′)—OC(═O)—R″ wherein R and R′ are each independently a hydrogen, an alkyl group and R″ is an alkyl group.R2 is:        a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 6 carbon atomsR3 and R4 are each independently:        a hydrogen        a phenyl or benzyl group, optionally substituted on the phenyl ring by:                    1 to 5 halogen atoms, particularly fluorine or bromine.            an OH, SH, OR″ or SR″ radical, R″ having the same definition as above.                            an amino group optionally mono- or di-substituted by a cyclic or linear aliphatic group having from 1 to 6 carbon atoms.                                    a trifluoromethyl group            an aromatic or heteroaromatic group having 5 or 6 atoms                        a heteroaromatic group having 5 or 6 atoms, containing 1 or 2 heteroatom(s) selected from oxygen, nitrogen or sulphur, wherein the sulphur and nitrogen atoms may be oxidized in S-oxide or N-oxide form.        a methylene substituted by an aromatic or saturated heterocycle having 5 or 6 atoms, the heteroatom being an oxygen, a nitrogen or a sulphur, wherein the nitrogen and sulphur atoms may be oxidized in N-oxide or S-oxide formR3 and R4 are not simultaneously a hydrogen atom.R5 and R6 are each independently        a hydrogen atom        a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 6 carbon atomsR7 is        a hydrogen        a CH2COOR′″ or CH(CH3)COOR′″ radical, R′″ being                    a saturated hydrocarbon chain having from 1 to 6 carbon atoms, optionally substituted by a C1 to C3 alkoxy group,            a C5 to C8 cycloalkyl group            a heteroaromatic phenyl, benzyl or alkyl group.                        a CH(R)O—C(O)OR′ or CH(R)OC(O)R′ group wherein R and R′ have the same definitions as above;or a pharmaceutically acceptable salt of said compounds for use in the treatment and/or prevention of eye pain.        
The compounds of the invention can advantageously be used to prevent or relieve eye pain, in particular dry eye syndrome. The compounds of the invention can advantageously be used to prevent or treat corneal neuropathic pain, in particular neuropathic hyperalgesia.